After decades of research, schizophrenia and related psychotic disorders are still among the most debilitating disorders in medicine. The chronic illness course in most individuals, greater treatment responsiveness during the first episode, progressive gray matter decline during early disease stages, and retrospective accounts of ‘prodromal’ or early illness signs and symptoms formed the basis for research on the psychosis risk syndrome (PRS), known variably as ‘clinical high risk’ (CHR), or ‘ultra-high risk’ (UHR), or ‘prodromal’. The pioneering era of research on PRS focused on the development and validation of specific assessment tools and the delineation of high risk criteria. This was followed by the examination of conversion rates in psychosis risk cohorts followed naturalistically, identification of predictors of conversion to psychosis, and investigation of interventions able to abort or delay the development of full psychosis. Despite initially encouraging results concerning the predictive validity of PRS criteria, recent findings of declining conversion rates demonstrate the need for further investigations. Results from intervention studies, mostly involving second-generation antipsychotics and cognitive behavioral therapy, are encouraging, but are currently still insufficient to make treatment recommendations for this early, relatively non-specific illness phase. The next phase of research on PRS, just now beginning, has moved to larger, ‘multisite’ projects to increase generalizability and to ensure that sufficiently large samples at true risk for psychosis are included. Emphasis in these emerging studies is on: 1) identification of biomarkers for conversion to psychosis; 2) examination of non-antipsychotic, neuroprotective and low-risk pharmacologic and non-pharmacologic interventions; 3) testing of potentially phase-specific interventions; 4) examination of the relationship between treatment response during PRS and prognosis for the course of illness; 5) follow-up of patients who developed schizophrenia despite early interventions and comparison of illness trajectories with patients who did not receive early interventions; 6) characterization of individuals with outcomes other than schizophrenia-spectrum disorders, such as bipolar disorder and remission from PRS, including false positive cases; and 7) assessment of meaningful social and role functioning outcomes. While the research conducted to date has already yielded crucial information, the translation of the concept of a clinically identifiable PRS into clinical practice does not seem justified at this point.